Abstract
Leucettines, a family of pharmacological inhibitors of dual-specificity tyrosine phosphorylation regulated kinases and cdc-like kinases (CLKs), are currently under investigation for their potential therapeutic application to Down syndrome and Alzheimer's disease. We here report that leucettine L41 triggers bona fide autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 cells, characterized by microtubule-associated protein light chain 3 membrane translocation and foci formation. Leucettine L41-triggered autophagy requires the Unc-51-like kinase and is sensitive to the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the mammalian target of rapamycin (mTOR)/PI3K-dependent pathway. Leucettine L41 does not act by modifying the autophagic flux of vesicles. Leucettine L41-induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited phosphatidylinositol-3-phosphate 5-kinase, FYVE domain-containing activity as tested both in vitro and in vivo, which may also contribute to autophagy induction. Altogether these results demonstrate that leucettines can activate the autophagic mTOR/PI3K pathway, a characteristic that may turn advantageous in the context of Alzheimer's disease treatment.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alzheimer Disease / drug therapy*
-
Alzheimer Disease / genetics
-
Alzheimer Disease / metabolism
-
Animals
-
Autophagy / drug effects*
-
Autophagy / genetics
-
Autophagy / immunology
-
Cell Line
-
Cell Line, Tumor
-
Dioxoles / pharmacology*
-
Dyrk Kinases
-
Enzyme Inhibitors / pharmacology*
-
Humans
-
Imidazoles / pharmacology*
-
Mice
-
Microtubule-Associated Proteins / genetics
-
Microtubule-Associated Proteins / metabolism
-
Osteosarcoma / drug therapy
-
Osteosarcoma / genetics
-
Osteosarcoma / metabolism
-
Phosphatidylinositol 3-Kinases / genetics
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Phosphorylation / drug effects*
-
Phosphorylation / genetics
-
Phosphorylation / immunology
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism
-
Protein-Tyrosine Kinases / genetics
-
Protein-Tyrosine Kinases / metabolism
-
TOR Serine-Threonine Kinases / genetics
-
TOR Serine-Threonine Kinases / metabolism*
-
Tyrosine / genetics
-
Tyrosine / metabolism*
Substances
-
((5Z)5-(1,3-benzodioxol-5-yl)methylene-2-phenylamino-3,5-dihydro-4H-imidazol-4-one)
-
Dioxoles
-
Enzyme Inhibitors
-
Imidazoles
-
Microtubule-Associated Proteins
-
Phosphoinositide-3 Kinase Inhibitors
-
Tyrosine
-
Protein-Tyrosine Kinases
-
Protein Serine-Threonine Kinases
-
TOR Serine-Threonine Kinases